How VE-PTP and Tie-2 regulate endothelial cell junctions in VE-cadherin dependent and independent ways

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The endothelial specific Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) is a receptor type tyrosine phosphatase (R-PTP) which is a major regulator of endothelial junctions, vascular permeability and leukocyte extravasation. We have shown that this phosphatase associates with and regulates the function of VE-cadherin, an adhesion molecule, which is of central importance for the integrity of endothelial junctions. In addition, we found that VE-PTP regulates the activity of the tyrosine kinase receptor Tie-2, which stabilizes junctions. Consequently, VE-PTP is a valuable pharmacological target for the stabilization of endothelial junctions and for the inhibition of inflammation induced vascular leak formation. Indeed, the highly specific inhibitor of VE-PTP, AKB9778, is able to protect from leak formation in inflammation models in the mouse and is presently tested successfully in phase II trials on diabetic retinopathy in patients. The purpose of this proposal is to elucidate the detailed mechanisms by which the inhibition of VE-PTP supports vascular integrity. We will analyze how the effects of VE-PTP on Tie-2 and VE-cadherin relate to each other and which other substrates and signaling targets of VE-PTP are involved in the regulation of endothelial junctions.